Since the discovery of endogenous opioid peptides in the 1970's, extensive research in opioid chemistry and biology have suggested the existence of multiple opioid receptors: .mu. (mu), .delta. (delta) and .kappa. (kappa).
The identification of multiple receptors is particularly interesting in that many opioids exert a variety of effects including analgesia, addiction, respiratory depression, inhibition of gut transit, and cardiotoxicity. See e.g., The Pharmacological Basis of Therapeutics, McMillan, pp. 496-536, New York (1980); Hruby et al., Med. Res. Rev. 9:343 (1989); and Zimmermann, et al., J. Med. Chem. 33:895 (1990).
Recent work has suggested that opioid peptides may also be involved in pathological states, including cancer. As shown in Table 1, multiple opioid receptors are present on numerous tumor cell lines.
While the exact role played by opioid peptides in oncogenic events remains unknown, opioids have been found to alter cell function and growth [Slotkin et al. Life Sci. 26:861 (1980); and Wilson et al. J. Pharmacol. Exp. Ther. 199:368 (1976)], to inhibit the growth of cultured neuroblastoma cells [Zagon et al. Brain Res. Bull. 7:25 (1981)], and to inhibit neuroblastoma tumor growth and
TABLE 1 ______________________________________ Opiate Receptor Binding-Tumors or Tumor Cell Lines* Opiate Receptor Conc. Tumor Receptor Subtype (fmol/mg protein) ______________________________________ Inventors' Data SCLC NCI-H69 mu 0 SCLC NCl-H69 delta 23 SCLC NCI-H69 kappa 0 A549 NSCLC mu 0 A549 NSCLC delta 0 A549 NSCLC kappa 0 MCF-7 mu 0 MCF-7 delta 23 MCF-7 kappa 0 M 5123 Hepatoma mu 0 B16 Melanoma mu 0 B16 Melanoma kappa 129 R3327 Prostate mu 0 Data from Maneckjee et al. Proc. Natl. Acad. Sci. USA 87:3294 (1990) SCLC NCI-H187 nonselective 450 SCLC NCl-H69 nonselective 202 SCLC NCI-H146 nonselective 172 SCLC NCI-N417 nonselective 39 SCLC NCI-H345 nonselective 18 NSCLC NCl-H322 nonselective 293 NSCLC NCI-H460 nonselective 194 NSCLC NCI-H157 nonselective 157 NSCLC NCl-H23 nonselective 119 NSCLC NCI-H290 nonselective 78 Data from Zagon et al. J. Natl. Cancer Inst. 79:1059 (1987) Breast Adenocarcinoma delta 8.3 Brent Adenocarcinoma mu 14.2 Breast Adenocarcinoma kappa 10.0 Overian Fibroma delta 225.0 Overian Fibroma kappa 15.5 Endometrial Adenocarcinoma delta 1.03 Endometrial Adenocarcinoma kappa 30.2 Rectal Adenocarcinoma delta 41.0 Rectal Adenocarcinoma kappa 54.0 ______________________________________ *does not exclude tumors expressing yet uncharacterized opiate receptor isotypes.
prolong survival times, in an opioid antagonist sensitive manner, in mice with transplanted neuroblastomas, B-16 melanoma, MCF-7 breast cancer, human lung cancer cells and others [Zagon et al. Life Sci. 28:1095 (1981); Zagon et al. Science 221:671 (1983); and Von Hoff et al. Proc., Am. Assoc. Cancer Res., Abstract 932, p. 236 (1982); Srisuchark et al. Int. J. Immunopharm. 11(5):487 (1989); Minna et al. Proc. Natl. Acad. Sci., 87:3294 (1990); ibid. 89:1169 (1992)].